Synthesis, dimeric crystal structure, and fungicidal activity of 1-(4-methylphenyl)-2-(5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-4-phenyl-4H-1,2, 4-triazol-3-ylthio)ethanone

Article abstract of DOI:10.1080/10426507.2010.508060

A new triazole compound, C₄₆H₄₆N₁₀O ₂S₂, has been synthesized, and the crystal structure was determined by a single crystal X-ray diffraction study. The fungicidal activity of the title compound was determined, and the results showed that it displays moderate fungicidal activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.508060

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Synthesis, Dimeric Crystal Structure,
and Fungicidal Activity of 1-(4-
Methylphenyl)-2-(5-((3,5-dimethyl-1H-
pyrazol-1-yl)methyl)-4-phenyl-4H-1,2,4-
triazol-3-ylthio)ethanone
Xing-Hai Liu a , Cheng-Xia Tan a & Jian-Quan Weng a
a College of Chemical Engineering and Materials Science , Zhejiang
University of Technology , Hangzhou, Zhejiang, China
Published online: 07 Mar 2011.
To cite this article: Xing-Hai Liu , Cheng-Xia Tan & Jian-Quan Weng (2011) Synthesis, Dimeric
Crystal Structure, and Fungicidal Activity of 1-(4-Methylphenyl)-2-(5-((3,5-dimethyl-1H-pyrazol-1-
yl)methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone, Phosphorus, Sulfur, and Silicon and the
Related Elements, 186:3, 558-564, DOI: 10.1080/10426507.2010.508060
To link to this article: http://dx.doi.org/10.1080/10426507.2010.508060
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Phosphorus, Sulfur, and Silicon, 186:558–564, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.508060
SYNTHESIS, DIMERIC CRYSTAL STRUCTURE, AND
FUNGICIDAL ACTIVITY OF 1-(4-METHYLPHENYL)-2-(5-
((3,5-DIMETHYL-1H-PYRAZOL-1-YL)METHYL)-4-PHENYL-
4H-1,2,4-TRIAZOL-3-YLTHIO)ETHANONE
Xing-Hai Liu, Cheng-Xia Tan, and Jian-Quan Weng
College of Chemical Engineering and Materials Science, Zhejiang University
of Technology, Hangzhou, Zhejiang, China
GRAPHICAL ABSTRACT
Abstract A new triazole compound, C46H46N10O2S2, has been synthesized, and the crystal
structure was determined by a single crystal X-ray diffraction study. The fungicidal activity of
the title compound was determined, and the results showed that it displays moderate fungicidal
activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Crystal structure; fungicidal activity; pyrazole; synthesis; triazole
Received 18 May 2010; accepted 9 July 2010.
This work was funded by National Natural Science Foundation of China (No. 21002090, 31000008,
30900959); the Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture (MOA), Beijing,
PR China (No. MOAPCA201005); Zhejiang Provincial Natural Science Foundation of China (Y3080096); and
Scientific Research Fund of Zhejiang Education Department (Y201018479).
Address correspondence to Xing-Hai Liu, College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou, 310014, Zhejiang, China. E-mail: xhliu@zjut.edu.cn
558

STUDY OF A 1,2,4-TRIAZOLE COMPOUND
559
INTRODUCTION
In recent years, theorganic compounds with heterocyclic ring systems have received
considerable attention1–5 because they, or their derivatives, have exhibited various types
of biological activities, and have thus been widely used by scientists or industries to de-
velop bioactive molecules for different purposes. Among them, nitrogen-heterocyclic com-
pounds6–8 are highly interesting due to their excellent pharmacological and pesticidal per-
formances. Notably, in this big family, 1,2,4-triazole– and pyrazole-based compounds play
a very important role. They have a rather wide bioactive spectrum. The 1,2,4-triazole–based
fungicides were first synthesized in the early 1970s. Their commercialized products were
successfully applied to protect various types of crops. Then in the following years, much
research went into efforts to develop other 1,2,4-triazole–based analogues. For instance, the
thione-substituted 1,2,4-triazole derivatives were developed to have a variety of biological
activities including fungicidal,9 insecticidal,10 bactericidal,11 herbicidal,6 and antitumor,12
as well as anti-inflammatory activities.13 For the pyrazole-based compounds, they are most
widely used as pesticides, and can also be utilized to develop antifungal14 and antibacterial15
properties as well. In view of these facts, mentioned above, we believe that the rational
combination of these two heterocycles should be a promising route to develop some novel
bioactive compounds. So in this article, we report the design and synthesis of a new group
of triazole-based compounds incorporated with pyrazole rings. The structure characteriza-
tions and the preliminary biological activity tests of these compounds were investigated as
well.
RESULTS AND DISCUSSION
Spectroscopic Properties
The IR spectrum of the title compound shows an absorption band at 1187 cm−1
,
which originated from the stretching vibration of the C S bond. The strong absorption
at 1674 cm−1 is assigned to the C O stretching vibration. The signal of C C aromatic
double bonds appeared at 1567, 1495, 1409 cm−1, which are at higher wave number region
than the typical aromatic C C absorption. This is induced by the conjugation of phenyl
ring and the neighboring C O group.
Crystal Structure
The single crystal of the title compounds was obtained, and its structure is shown
in Figure 1 The selected bond lengths and bond angles of the single crystal diffraction
experiment on this compound are listed in Table 1. The π–π stacking pattern is shown
in Figure 2. Torsion angles and a packing diagram are shown in Table S1 and Figure S1,
respectively (Supplemental Materials, available online).
As shown in Figure 1, the acetyl group is nearly planar with the thio-ether group with
a quite small dihedral angle (θ) of 3.41◦. The triazole ring (N3, N4, C8, N5, C7) with atoms
S1, C6, and C9 (pyrazole ring (N1, N2, C4, C3, C2) with atoms (C1, C5, and C6) is fairly
planar with plane equation −5.007x + 7.767y − 11.923z = −7.046 (3.553x + 7.177y +
14.229z = 10.6997), and the largest deviation from the least squares plane is 0.00005 nm
(0.00612 nm). Meanwhile, the triazole ring is vertical with both the phenyl ring (C9∼C14)
and the pyrazole ring with the respective dihedral angles of 98.6◦ and 95.4◦. In contrast, it

560
X.-H. LIU ET AL.
Figure 1 Molecular structure of the title compound, showing displacement ellipsoids drawn at the 30% probability
level.
is nearly planar withanother phenyl ring (C17∼C22) with the dihedral angle of 163.8◦. A
summary of the key crystallgraphic information is given in Table 2.
In the intermolecular face-to-face π–π stacking pattern of the title compound
(Figure 2), it is worth mentioning that the two molecules of each stacking unit are centrosym-
metric, which can be proved by the relative position of the two phenyl rings (C40∼C45) of
the two molecules. Their centroid separation is 3.577 Å, and their dihedral angle is 21.84◦.
Another interesting feature is the intermolecular edge-to-face π–π stacking, which exists
between the phenyl ring C40∼C45 and the phenyl ring C17∼C22 of the adjacent molecule
(Figure S1, Supplemental Materials The distance of H23C and the centroid of phenyl ring
Figure 2 (a) Face-to-face π–π stacking; (b) edge-to-face π–π stacking.

STUDY OF A 1,2,4-TRIAZOLE COMPOUND
561
Table 1 Selected bond lengths (Å) and angles (◦) for the title compound
◦
Bond lengths
Å
Bond angles
S(1) C(8)
S(1) C(15)
S(2) C(31)
S(2) C(38)
O(1) C(16)
O(2) C(39)
N(1) C(2)
N(1) N(2)
N(2) C(4)
N(2) C(6)
N(3) C(7)
N(3) N(4)
N(4) C(8)
N(5) C(8)
N(5) C(7)
N(5) C(9)
N(6) C(25)
N(6) N(7)
N(7) C(27)
N(7) C(29)
N(8) C(30)
N(8) N(9)
N(9) C(31)
N(10) C(31)
N(10) C(30)
1.737(3)
1.802(2)
1.736(3)
1.800(2)
1.214(3)
1.216(3)
1.337(3)
1.368(2)
1.352(3)
1.455(3)
1.298(3)
1.405(3)
1.320(3)
1.367(3)
1.375(3)
1.431(3)
1.324(3)
1.362(3)
1.356(3)
1.447(3)
1.301(3)
1.403(3)
1.309(3)
1.370(3)
1.373(3)
C(8) S(1) C(15)
C(31) S(2) C(38)
C(2) N(1) N(2)
C(4) N(2) N(1)
C(4) N(2) C(6)
N(1) N(2) C(6)
C(7) N(3) N(4)
C(8) N(5) C(9)
C(7) N(5) C(9)
C(25) N(6) N(7)
C(27) N(7) N(6)
C(27) N(7) C(29)
N(6) N(7) C(29)
C(30) N(8) N(9)
C(31) N(9) N(8)
C(31) N(10) C(30)
C(31) N(10) C(32)
C(30) N(10) C(32)
N(1) C(2) C(3)
N(1) C(2) C(1)
N(2) C(4) C(3)
N(2) C(4) C(5)
N(3) C(7) C(6)
N(4) C(8) S(1)
N(5) C(8) S(1)
97.39(12)
98.41(13)
103.8(2)
112.8(2)
128.0(2)
118.9(2)
107.4(2)
128.3(2)
126.8(2)
104.6(2)
112.2(3)
129.2(3)
118.6(2)
107.5(2)
106.5(2)
104.2(2)
127.1(2)
128.6(2)
110.9(2)
119.8(3)
105.7(3)
123.5(3)
125.6(2)
127.4(2)
122.0(2)
(C40∼C45) is 2.703 Å, and the angle of C23–H23C and the phenyl centroid is 145.14◦.
These interactions are estimated to play a role in stabilizing the crystal structure.
The average bond lengths and bond angles of ring systems (phenyl, pyrazole, and
triazole) are normal: the C H bond lengths are in the range of 0.93–0.97Å; the C O, C S
bond lengths (C16-O1 = 1.214(3) Å and C15-S1 = 1.802(2) Å) are comparable with those
reported in the literature.16
EXPERIMENTAL
Melting points were determined using an X-4 apparatus without calibration. Infrared
1
spectra were recorded on a Bruker Equinox55 spectrophotometer using KBr tablets. H
NMR spectra were measured on a Bruker AC-P500 instrument (300 MHz) using TMS as an
internal standard and CDCl3 as solvent. Mass spectra were recorded on a Thermo Finnigan
LCQ Advantage LC/mass detector instrument. Elemental analyses were performed on
a Yanaco MT-3CHN elemental analyzer. Crystallographic data of the compound were
collected on a Bruker SMART 1000 CCD diffractometer.
Preparation
The title compound was synthesized as shown in Scheme 1.

562
X.-H. LIU ET AL.
Scheme 1 The synthetic route of the title compound.
3,5-Dimethyl-1H-pyrazole (1)
A mixture of acetylacetone (7.0 g, 0.12 mol) and hydrazine hydrate (7.0 g, 85%)
was refluxed for 3 h in alcohol. After the reaction was finished, the solvent alcohol was
evaporated to afford compound 1 as a white crystal with 82.2% yield, mp 97–98◦C (Ref.17
96–98◦C).
Table 2 Crystal structure and data refinement parameters
Compound
6
Empirical formula
Formula weight
C46H46N10O2S2
835.05
Crystal system/space group
a/Å
b/Å
Monoclinic, P2(1)/c
18.069 (3)
11.1394 (17)
22.791 (4)
90
110.386 (3)
90
4299.9 (12)
4
c/Å
α/◦
β/◦
γ /◦
V/Å3
Z
Dcalc (g/cm3)
1.290
0.1800
µ (mm−1
)
Crystal size (mm)
Color/shape
Temp (K)
0.26 × 0.24 × 0.20
Colorless/prism
294(2)
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
2.2–21.1
23796
8799
8799/0/547
1.012
R1 = 0.0477, wR2 = 0.0783
R1 = 0.1548, wR2 = 0.1003
0.208 and −0.208
Largest difference peak/hole

STUDY OF A 1,2,4-TRIAZOLE COMPOUND
563
Ethyl 2-(3,5-Dimethyl-1H-pyrazol-1-yl)acetate (2)
Compound 1 (4.8g, 50 mmol) and K2CO3 (6.91 g, 50 mmol) was dissolved in acetone
(25 mL), then ethyl chloroacetate (6.13 g, 50 mmol) was added dropwise. The resulting
mixture was stirred for 18 h at reflux temperature, and the precipitate that formed was
collected afterward by filtration. The crude product was purified by silica-packed flash
column chromatography (eluented with EA:PE = 1:1mixture). Yield 53.4%. 1H NMR (400
M, CDCl3) 5.85 (s, PyH, 1H), 4.75 (s, N CH2, 2H), 4.21 (q, OCH2CH3, 2H), 2.21 (s,
Py CH3, 3H), 2.20 (s, Py CH3, 3H), 1.27 (q, OCH2CH3, 3H).
2-(3,5-Dimethyl-1H-pyrazol-1-yl)acetohydrazide (3)
Hydrazine hydrate (100%, 30 mol) was added dropwise into a solution of compound 2
(20 mmol) in ethanol (15 mL), and then the mixture was stirred for 2 h at room temperature.
Next, the mixture was filtered, and the pure compound 3 was crystallized from ethanol as
a white solid in 86% yield. Mp 199–202◦C(Ref.18 198–199◦C).
2-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)acetyl)-N-
phenylhydrazinecarbothioamide (4)
To a solution of compound 3 (1.68 g, 10 mmol) in ethanol (40 mL), isothiocyanato-
benzene (1.35 g, 10 mmol) was added dropwise over a period of 15 min at room temperature,
then the mixture was refluxed for an additional 4 h. The product 4 was collected by filtration.
5-((3,5-Dimethyl-1H-pyrazol-1-yl)methyl)-4-phenyl-4H-1,2,4-triazole-
3-thiol (5)
To an aqueous solution of sodium hydroxide (1.2 g, 30 mmol, 2N), compound 4 (3 g,
10 mmol) was added dropwise. The mixture was refluxed for 4 h. After being cooled down
to room temperature, the solution was neutralized by HCl(4N). The product was obtained
by filtration. Yield 95.6%, mp >260◦C.
2-((5-((3,5-Dimethyl-1H-pyrazol-1-yl)methyl)-4-phenyl-4H-1,2,4-
triazol-3-yl)thio)-1-(p-tolyl)ethanone (6)
A solution of p-methylphenacyl bromide (0.42 g, 2 mmol) in ethanol (8 mL) was
added dropwise into the solution of compound 5 (1.71g, 6 mmol) in ethanol (10 mL) with
stirring. The resulting mixture was refluxed for 1 h. The precipitate was recrystallized from
1
ethanol to give compound 6 as a white crystal in 62.3% yield, mp 122–123◦C; H NMR
(CDCl3, 300 MHz), δ: 7.65 (d, J = 8.4, ArH(6), 1H), 7.45 (d, Jac = 1.9, ArH(3), 1H), 7.34
(dd, Jab = 8.4, Jac = 2.0, ArH(5), 1H), 5.39 (s, Py CH2, 2H), 4.71 (s, S CH2, 2H), 3.73
(s, N CH3, 3H), 2.75 (s, Py CH3, 3H), 2.49 (s, Py CH3, 3H). IR (KBr), ν/cm−1: 1674,
1567, 1495, 1409, 1187. MS (ESI), m/z: 418 (M + 1). Elemental anal. (%), calculated: C,
44.62; H, 3.60; N, 18.42; found: C, 44.84; H, 3.54; N, 18.46.
Crystal Structure Determination
The prism-shaped single crystal of the title compound was obtained by recrystalliza-
tion from EtOH. The crystal with dimensions of 0.26 mm × 0.24 mm × 0.20 mm was

564
X.-H. LIU ET AL.
mounted on a Bruker SMART 1000 CCD area-detector diffractometer with a graphite-
monochromated MoKα radiation (λ = 0.71073Å) by using a Phi scan modes at 294(2) K
in the range of 2.2◦ ≤ θ ≤ 21.10◦. A total of 23,796 reflections were collected, of which
8799 were independent (Rint = 0.0682) and 3741 were observed with I > 2σ(I). The
calculations were performed with the SHELXS-97 program,19 and the empirical absorp-
tion corrections were applied to all intensity data. The nonhydrogen atoms were refined
anisotropically. The hydrogen atoms were determined with theoretical calculations and
refined isotropically. The final full-matrix least squares refinement gave R = 0.0477 and
wR = 0.0783 (w = 1/[s2(Fo ) + (0.0286P)2], where P = (Fo + 2Fc )/3, S = 1.01,
(ꢀ/σ)max = 0.0040, ꢀρmax = 0.21, and ꢀρmin = −0.21 e Å−3. Atomic scattering factors
and anomalous dispersion corrections were taken from the International Table for X-Ray
Crystallography.20
2
2
2
CCDC-775280 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk.
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